Tran Kristine M, Kwang Nellie, Gomez-Arboledas Angela, Kawauchi Shimako, Mar Cassandra, Chao Donna, Da Cunha Celia, Wang Shuling, Collins Sherilyn, Walker Amber, Shi Kai-Xuan, Alcantara Joshua A, Neumann Jonathan, Tenner Andrea J, LaFerla Frank M, Hohsfield Lindsay A, Swarup Vivek, MacGregor Grant R, Green Kim N
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
bioRxiv. 2024 Jun 4:2024.06.03.597211. doi: 10.1101/2024.06.03.597211.
Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.
We introduced the R136S variant into mouse () and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial transcriptomics and proteomics to explore the impact of the variant on AD pathological development and the brain's response to plaques and tau.
In 5xFAD mice, enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by . We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of .
These findings highlight the ability of the variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.
载脂蛋白Eε4（APOE4）是晚发性阿尔茨海默病（LOAD）最强的遗传风险因素。最近一份病例报告在APOE中鉴定出一种罕见变体APOE3-R136S（克赖斯特彻奇变体），该变体被认为可赋予对常染色体显性阿尔茨海默病（AD）的抗性。然而，目前尚不清楚该变体是否以及如何发挥其保护作用。
我们将R136S变体引入小鼠，并使用淀粉样变性的5xFAD模型和tau病变的PS19模型研究其对AD相关病理发展的影响。我们使用免疫组织化学和生化分析以及单细胞空间转录组学和蛋白质组学来探索该变体对AD病理发展以及大脑对斑块和tau的反应的影响。
在5xFAD小鼠中，该变体增强了斑块周围小胶质细胞中与疾病相关的小胶质细胞（DAM）表型，并减少了斑块负荷、营养不良性神经突和血浆神经丝轻链。相比之下，在PS19小鼠中，该变体抑制了小胶质细胞和星形胶质细胞对富含tau的神经元的反应，并且不会减少tau的积累或磷酸化，但部分挽救了tau诱导的突触和髓鞘损失。我们比较了两种小鼠模型中小胶质细胞反应的差异，以阐明该变体诱导的不同DAM特征。我们发现，与5xFAD背景相比，PS19背景下DAM反应中抗原呈递相关基因上调，这表明对淀粉样蛋白与tau病理的反应存在差异，且这种差异受该变体的存在调节。
这些发现突出了该变体根据病理类型调节小胶质细胞反应的能力，在淀粉样蛋白模型中增强DAM反应性，并在tau模型中减轻神经炎症以促进保护。这表明克赖斯特彻奇变体的保护作用可能涉及多种机制，包括受体结合和小胶质细胞编程的变化。
